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Abstract

Background—Animal experiments and epidemiological studies have suggested that high potassium intake may reduce the risk of stroke, but the evidence is inconclusive, and the role of other nutrients in potassium-rich foods remains unknown.

Methods and Results—We examined the association of potassium and related nutrients with risk of stroke among 43 738 US men, 40 to 75 years old, without diagnosed cardiovascular diseases or diabetes, who completed a semiquantitative food frequency questionnaire in 1986. During 8 years of follow-up, 328 strokes (210 ischemic, 70 hemorrhagic, 48 unspecified) were documented. The multivariate relative risk of stroke of any type for men in the top fifth of potassium intake (median intake, 4.3 g/d) versus those in the bottom (median, 2.4 g/d) was 0.62 (95% CI, 0.43, 0.88; P for trend=0.007). Results for ischemic stroke alone were similar. Intakes of cereal fiber and magnesium, but not of calcium, were also inversely associated with risk of total stroke. These inverse associations were all stronger in hypertensive than normotensive men and were not materially altered by adjustment for blood pressure levels. Use of potassium supplements was also inversely related to risk of stroke, particularly among men taking diuretics (relative risk, 0.36; 95% CI, 0.18, 0.72).

Conclusions—Although these data do not prove a causal relationship, they are consistent with the hypothesis that diets rich in potassium, magnesium, and cereal fiber reduce the risk of stroke, particularly among hypertensive men. Potassium supplements may also be beneficial, but because of potential risks, use should be carefully monitored and restricted to men taking potassium-losing diuretics.

A role for potassium in determining risk of stroke is suggested by epidemiological studies1234 and animal experiments.5 A beneficial effect of potassium intake could be due to its hypotensive effect,67 but this is small, and neither in rats5 nor in humans14 could it explain the reduced risk of stroke. Other mechanisms that have been suggested include inhibition of free radical formation,8 vascular smooth muscle proliferation,9 and arterial thrombosis.10

However, the overall evidence is unconvincing. Small size and inadequate dietary assessment are among the limitations of the previous epidemiological studies, because diet based on a single 24-hour recall was used to predict stroke incidence over a 12-,1 16-,2 or 20-year period.4 This dietary assessment reduces the ability to adjust for consumption of other foods or nutrients that may explain the inverse associations reported.11 To overcome this limitation, we addressed the hypothesis that high potassium intake reduces the risk of stroke in a large cohort of men who completed a detailed and validated semiquantitative food frequency questionnaire at baseline and were followed up for 8 years. In addition, we examined the associations between risk of stroke and intakes of dietary fiber, magnesium, and calcium, which are correlated with intake of potassium and may be related to risk of stroke.

Methods

Population

The Health Professionals Follow-up Study began in 1986, when 51 529 health professionals 40 to 75 years old12 completed a 131-item food-frequency questionnaire and provided information about medical history and lifestyle. Follow-up questionnaires were sent every 2 years to update information on potential risk factors and to identify newly diagnosed cases of stroke and other diseases. We excluded from analysis 1595 men who did not satisfy the a priori criteria of daily caloric intake between 800 and 4200 kcal and <70 blanks out of 131 total listed food items. In addition, we excluded men with prior diagnosis of myocardial infarction, angina, coronary artery surgery, stroke, transient ischemic attack, peripheral arterial disease, or diabetes. We followed up the 43 738 eligible men for stroke incidence during the subsequent 8 years. The average response rate for the 2-year follow-up cycles was >94%. Nonresponding participants not matched to the National Death Index were assumed to be alive.

Assessment of Diet and Other Exposure Variables

The 1986 questionnaire asked about average frequency of intake during the previous year of specified portions of 131 foods and use of vitamin and mineral supplements. Nutrient calculations took into account the specific brand of breakfast cereal and multivitamins reported by each subject. We also asked about use of specific supplements of potassium and magnesium (apart from multivitamins). We assumed the amount of potassium in these specific supplements to be 1 g/d and that of magnesium 0.3 g/d, because details on doses were not asked in the questionnaire. We assessed the validity of the questionnaire in a random sample of 127 men who completed two 1-week diet records.13 The correlations between the 2 assessments of intake, energy-adjusted and corrected for within-person variation in the diet records, were 0.65 for potassium, 0.64 for dietary fiber, 0.66 for magnesium, and 0.53 for calcium. In addition to diet, in 1986, participants were asked to report their usual systolic and diastolic blood pressure and whether or not they had physician-diagnosed hypertension. The validity of these variables has been documented previously.14

Cases

End points were fatal and nonfatal strokes occurring between the return of the baseline questionnaire and January 31, 1994. Participants reporting an incident stroke on a follow-up questionnaire were asked for permission to review medical records. Strokes were confirmed if characterized by a typical neurological defect of sudden or rapid onset, lasting ≥24 hours and attributable to a cerebrovascular event. Strokes caused by infection or neoplasia were excluded. Reviews were conducted by physicians with no knowledge of the subjects’ risk factor status. Strokes were subclassified according to the criteria of the National Survey of Stroke as due to ischemia (embolism or thrombosis), subarachnoid hemorrhage, intracerebral hemorrhage, or unknown cause.15 If no records could be obtained, strokes were considered probable if they required hospitalization and were corroborated by additional information provided by letter or interview.

Deaths were reported by next of kin, coworkers, postal authorities, or the National Death Index. Fatal strokes were confirmed by medical records or autopsy reports or were considered probable if these were not obtainable and stroke was listed as the underlying cause on the death certificate.

Statistical Analysis

Participants contributed follow-up time from the return of the 1986 questionnaire up to the occurrence of a confirmed stroke, death, or January 31, 1994. The occurrence of nonfatal cardiovascular events, such as myocardial infarction or coronary surgery, was not a reason for censoring. Intakes of potassium and other nutrients were energy-adjusted to 2000 kcal/d.16 Relative risks (RR) were calculated by dividing the incidence of stroke among men in each fifth of energy-adjusted potassium intake at baseline by the incidence among men in the lowest fifth of intake. Similar calculations were done for the other nutrients. We adjusted RRs for age (5-year categories)17 and used the Mantel extension test18 to test for linear trends. To adjust for other risk factors, we used pooled logistic regression with 2-year intervals. When the probability of an event within an interval is small, this method is equivalent to a Cox proportional-hazards analysis.19 Multivariate models included as covariates calendar time (2-year intervals), total energy intake (continuous variable), smoking (current, past, and 1 to 14, 15 to 24, and ≥25 cigarettes/d), alcohol consumption (<5, 5 to 9, 10 to 14, 15 to 29, and ≥30 g/d), history of hypertension, history of hypercholesterolemia, parental history of myocardial infarction before age 65 years, profession, and quintiles of body mass index and physical activity. In these models, we evaluated monotonic trends by using the median value of each category and modeling this as a continuous variable. All P values are 2-sided. Covariates were not updated during the follow-up.

Results

During 323 394 person-years of follow-up, we documented 328 cases of cerebrovascular accidents (50 fatal), including 210 ischemic, 70 hemorrhagic, and 48 unclassified strokes. Men in the top fifth of potassium intake (including potassium from supplements) were less likely to smoke, were more physically active, and consumed less alcohol, less fat, more protein, and more micronutrients than men in the bottom fifth (Table 1⇓). Similar relations were found for magnesium, fiber, and calcium (data not shown). The age-adjusted RR of total stroke for men in the top fifth of potassium intake compared with those in the bottom fifth was 0.59 (Table 2⇓). This RR was slightly attenuated by adjustment for nondietary risk factors (RR=0.62) and by further adjustment for intakes of magnesium and dietary fiber (RR=0.69). The corresponding associations with ischemic stroke were similar, whereas no significant associations were observed for hemorrhagic stroke (data not shown). Further adjustment for intakes of total fat, protein, saturated fat, vitamin C, vitamin E, carotene, or folic acid did not materially change the association between potassium intake and risk of total stroke, nor did adjustment for baseline systolic and diastolic blood pressure or addition to the model of an interaction term between age and hypertension.

RR of Stroke According to Intake of Potassium, Total Fiber, Magnesium, and Calcium Adjusted by Energy

Intakes of dietary fiber and magnesium were both inversely associated with risk of total stroke in age-adjusted analyses (Table 2⇑). These associations were only moderately attenuated by adjustment for nondietary risk factors, but they were substantially weakened in regression models that simultaneously included potassium, magnesium, and dietary fiber because of the positive correlations between intakes of these nutrients (Pearson correlation coefficients were 0.65 for magnesium and potassium, 0.62 for magnesium and fiber, and 0.58 for potassium and fiber).

Neither calcium nor sodium intake (data not shown) was significantly associated with risk of total, ischemic, or hemorrhagic stroke. Sodium intake was also unrelated to intake of potassium (Pearson correlation = −0.02) and was not analyzed further. Because in a previous investigation an inverse association was reported between calcium from dairy sources and risk of stroke,20 we examined this relationship in our cohort. The multivariate risk for the top compared with the bottom quintile of dairy calcium intake was 0.83 (95% CI, 0.59, 1.17) for total (Table 2⇑), 0.90 (95% CI, 0.59, 1.37) for ischemic, and 0.73 (95% CI, 0.36, 1.51) for hemorrhagic stroke; the lowest incidence of each outcome was observed in the middle quintile of intake. Also, we examined whether the risk of stroke was lower among men who reported using calcium supplements at baseline. The RR for men who took ≥400 mg/d of supplemental calcium compared with nonusers was 0.88 for total stroke (95% CI, 0.60, 1.27) and 0.83 for ischemic stroke (95% CI, 0.52, 1.34).

When intakes of dietary fiber from different sources were considered separately, only cereal fiber was inversely associated with risk of stroke. This association remained after adjustment for potassium, magnesium, and fiber from other sources; both potassium and cereal fiber intake appeared to be independently inversely associated with risk of total stroke (Figure 1⇓). Intakes of fruits, vegetables, and cereal products were each inversely associated with risk of total stroke, but none of these associations were significant. The multivariate RR for an increase of 1 serving per day was 0.96 (95% CI, 0.89, 1.03; P for trend=0.26) for fruits, 0.96 (95% CI, 0.91, 1.02; P for trend=0.18) for vegetables, and 0.94 (95% CI, 0.87, 1.02; P for trend=0.11) for cereal. Results for ischemic stroke were similar.

We further examined separately the associations of potassium and magnesium from supplements with risk of stroke. Neither use of potassium supplements (RR=0.78; 95% CI, 0.69 to 1.22) nor use of magnesium supplements (RR=0.85; 95% CI, 0.55 to 1.32) was associated with risk of total or ischemic stroke in analyses adjusted for age only, but use of potassium supplements became strongly inversely associated after adjustment for history of hypertension (RR=0.55; 95% CI, 0.35 to 0.86). History of hypertension was a strong independent risk factor for stroke (RR=2.8; 95% CI, 2.1, 3.7) and was associated with use of potassium supplements (46% of the 1248 supplement users were hypertensives, compared with 19% of nonusers). The inverse association between use of potassium supplements and risk of stroke in multivariate analyses was independent of dietary intakes of nutrients, including potassium, magnesium, and fiber, and was stronger among men with low dietary intake of potassium, magnesium, and cereal fiber. The RR comparing the top with the bottom quintile of potassium intake was 0.39 in the lowest tertile of a dietary score, including the 3 nutrients, 0.57 in the middle, and 0.86 in the highest tertile. To further test the hypothesis that use of potassium supplements reduces the risk of stroke, we compared men who reported using supplements both in 1986 and 1988 with men who never used supplements. During the 6 remaining years of follow-up, the multivariate RR of total stroke among supplement users was 0.31 (95% CI, 0.12, 0.85; P=0.02); the risk of stroke was also reduced among men who reported using potassium supplements only in 1986 (0.46; 95% CI, 0.22, 0.98; P=0.05) but not among men who started taking supplements in 1988 (1.07; 95% CI, 0.55, 2.11).

Because of the importance of hypertension as a risk factor for stroke, we conducted analyses stratified by history of hypertension at baseline. Inverse associations between nutrient intakes and risk of stroke were observed only among hypertensive men (Figures 2⇓ and 3⇓). In analyses restricted to men taking diuretics at baseline, alone or in combination with other antihypertensive drugs, the RR of stroke for users of potassium supplements compared with nonusers was 0.36 (95% CI, 0.18, 0.72; P=0.004). Both fiber and cereal fiber were significantly inversely associated with risk of stroke among hypertensive (RRs for a 10-g increase in intake were 0.59 and 0.33, respectively) but not among normotensive (RRs were 0.88 for both) men.

Multivariate RR of total stroke according to intake of potassium and magnesium supplements. Top, Men without history of hypertension; bottom, men with history of hypertension.

Discussion

In this large prospective study, we found that men with diets higher in potassium, cereal fiber, and magnesium had a substantially reduced risk of stroke. These inverse associations were only partly explained by nondietary risk factors but were strong and significant only among men with diagnosed hypertension. No significant associations were found between intakes of sodium and calcium and risk of stroke.

A protective effect of potassium intake on risk of stroke would be consistent with the reduced risk that we observed among hypertensive men taking potassium supplements in the present study and with the findings of a previous epidemiological investigation1 and experiments with hypertensive rats.521 In a separate cohort among Japanese men in Hawaii, potassium intake was inversely related to risk of fatal thromboembolic stroke (RR for the top versus the bottom quintile of intake=0.3, P for trend=0.002) but not with risk of nonfatal thromboembolic stroke (RR=0.87, P for trend=0.12).2 The weak association with nonfatal events is not inconsistent with a protective effect, which may have been diluted by error in the single 24-hour recall– based dietary assessment. In randomized trials, high potassium intake has caused modest reduction in blood pressure, especially among hypertensive subjects.67 This effect, however, is small and could only partially explain the strong inverse association observed in this study. In addition, adjustment for baseline blood pressure levels had little effect on the estimated RRs relating potassium intake to stroke incidence, and potassium intake was not a significant predictor of risk of hypertension within this cohort.14 Alternative mechanisms proposed include the inhibition of free radical formation, vascular smooth muscle proliferation, and arterial thrombosis.22 However, these effects were produced by experimental increases in serum potassium concentrations in animals, and their relevance to humans is uncertain. High potassium intake may increase serum concentrations, particularly when intake is low or sodium intake is high,22 and could therefore reduce the risk of hypokalemia among men at high risk because of diuretic treatment. Diuretic-induced hypokalemia may increase the risk of ventricular dysrhythmia.2324 Although no increased mortality from cardiovascular disease or other causes was found among men with low serum potassium in 2 previous studies,2526 neither was large enough to detect a specific association between serum potassium and risk of stroke.

Intakes of magnesium and fiber were also inversely associated with risk of stroke, but their correlation with intake of potassium and measurement errors reduced the ability of multivariate analyses to discriminate between them. This difficulty is compounded by the fact that some previous epidemiological evidence and biological plausibility can be invoked for a beneficial effect of any of these nutrients, although only potassium has been shown to directly reduce risk of stroke in animal models. In a cross-sectional study, magnesium intake has been found to be inversely associated with carotid artery thickness in women but not in men.27 Also, there are reports that magnesium deficiency increases susceptibility of lipoproteins to peroxidation in rats.28 Conversely, magnesium supplementation failed to reduce blood pressure in randomized trials among normotensive subjects,729 and high-magnesium diets have been reported to increase rather than decrease the risk of stroke in hypertensive rats.30 In a randomized trial in China, a multiple vitamin/mineral supplement containing 200 mg of magnesium reduced the risk of stroke among men, but this effect may have been due to 1 of the several other micronutrients included in the supplement.31 Intake of fiber, particularly cereal fiber, has been shown to be inversely related to risk of coronary heart disease in most prospective investigations.323334 These results strongly suggest that high fiber intake inhibits the development of atherosclerosis or thrombosis and indirectly support a preventive effect of fiber on risk of ischemic stroke. Mechanisms for these beneficial effects, however, remain largely elusive.33

The lack of association between sodium intake and risk of stroke in our study may be due to the difficulty in measuring sodium intake accurately and to the scarcity of men with low or very high intake and does not in itself contradict the hypothesis that substantial reductions in intake decrease risk.35363738 Although measurement error also may have affected the results on calcium, our data do not support the previously reported inverse association between calcium consumption and risk of stroke.20 In hypertensive rats, high calcium intake provided partial protection against salt-induced stroke, decreasing lesion size but increasing lesion number,39 whereas in rabbits it prolonged clotting time and reduced the severity of atherosclerosis.40 The relevance of these observations to humans, however, remains to be established.

In conclusion, although these data do not prove a causal relationship, they provide strong support for a preventive effect of diets rich in potassium, magnesium, and cereal fiber on stroke, particularly among men with high blood pressure. Increased intake of potassium alone may decrease the risk of stroke, and perhaps potassium supplements for hypertensives should be more broadly considered. However, evidence is inadequate to support an indiscriminate use of potassium supplements, which can be harmful.41 Rather, potassium intake should be increased by substituting fruits, vegetables, and their natural juices for low-potassium processed foods and sodas.

Acknowledgments

This study was supported by research grants HL-35464 and CA-55075 from the National Institutes of Health. Dr Ichiro Kawachi is supported by a Career Development Award from the NHLBI. We are indebted to the participants of the Health Professionals Follow-up Study; to Al Wing, Mira Kaufman, Karen Corsano, and Steve Stuart for computer assistance; to Jill Arnold, Betsy Frost-Hawes, Kerry Demers, and Mitzi Wolff for their assistance in the compilation of data and the preparation of the manuscript; and to Laura Sampson and Helaine Rockett for maintaining our food composition tables.